Drug Class Description
Bisphosphonates.

Generic Name
Etidronate disodium

Drug Description
Each tablet contains 200mg of Etidronate Disodium, USP

Presentation
White rectangular tablets marked with 'P&G' on one face and '402' on the other.

Indications
Paget's disease of bone:Effectiveness has been demonstrated primarily in patients with polyostotic Paget's disease with symptoms of pain and with clinically significant elevations of urinary hydroxyproline and serum alkaline phosphatase. In other circumstances in which there is extensive involvement of the skull or the spine with the prospect of irreversible neurological damage, or when a weight-bearing bone may be involved, the use of Didronel may also be considered.

Adult Dosage
5mg/kg/day to 20mg/kg/day as detailed below.Didronel should be given on an empty stomach. It is recommended that patients take the therapy with water, at the mid point of a four hour fast (ie. two hours before and two after food).Adults and Elderly:The recommended initial dose of Didronel for most patients is 5mg/kg body weight/day, for a period not exceeding six months. Doses above 10mg/kg should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget's disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10mg/kg/day should be approached cautiously and should not exceed three months duration. Doses in excess of 20mg/kg/day are not recommended.Re-treatment should be undertaken only after a drug-free period of at least three months and after it is evident that reactivation of the disease has occurred and biochemical indices of the disease have become substantially re-elevated or approach pretreatment values (approximately twice the upper limit of normal or 75% of pre-treatment value). In no case should duration of treatment exceed the maximum duration of the initial treatment. Premature re-treatment should be avoided. In clinical trials the biochemical improvements obtained during drug therapy have generally persisted for a period of three months to 2 years after drug withdrawal.Daily Dosage GuideBody WeightRequired Daily Regimen of 200mg TabletsKilogramesStones5mg/kg*10mg/kg*20mg/kg+508135609.523670112478012.52489014259*Course of therapy - 6 months+Course of therapy - 3 months

Child Dosage
Disorders of bone in children, referred to as juvenile Paget's disease, have been reported rarely. The relationship to adult Paget's disease has not been established. Didronel has not been studied in children for Paget's disease.

Contra Indications
Known hypersensitivity to the drug. Clinically overt osteomalacia.

Special Precautions
In Pagetic patients the physician should adhere to the recommended dose regimen in order to avoid over- treatment with Didronel. The response to therapy may be of slow onset and may continue even for months after treatment with the drug has been discontinued. Dosage should not be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process. Re-treatment should not be initiated until the patient has had at least a three-month drug-free interval.Didronel is not metabolised but excreted unchanged via the kidney; therefore, a reduced dose should be used in patients with mild renal impairment and treatment of patients with moderate to severe renal impairment should be avoided. Caution should be taken in patients with a history of renal stone formation. In patients with impaired renal function or a history of renal stone formation, serum and urinary calcium should be monitored regularly.It is recommended that serum phosphate, serum alkaline phosphatase and if possible urinary hydroxyproline be measured before commencing medication and at three month intervals during treatment. If after three months of medication the pre-treatment levels have not been reduced by at least 25%, the patient may be relatively resistant to therapy. If the serum phosphate level is unchanged in the "resistant" patient, consideration should be given to increasing the dose since the absorption of pharmacologically active amounts of Didronel is typically accompanied by a rise in serum phosphate. This rise usually correlates with reductions in the biochemical indices of disease activity. If after three or more months of medication elevations of serum phosphate above the upper limit of normal are not accompanied by clinical or biochemical evidence of reduced activity, resistance of the disease to the action of Didronel is probable and termination of Didronel medication should be considered. Etidronate disodium suppresses bone turnover and may retard mineralisation of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10-20 mg/kg/day, mineralises normally post-therapy. Patients in whom serum phosphate elevations are high and reductions of disease activity are low may be particularly prone to retarded mineralisation of new osteoid. In those cases where 200mg per day (a single tablet) may be excessive, doses may be administered less frequently.Patients with Paget's disease of bone should maintain an adequate intake of calcium and vitamin D. Patients with low vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely monitored during Didronel therapy.Etidronate disodium does not adversely affect serum levels of parathyroid hormone or calcium.Hyperphosphataemia has been observed in patients receiving etidronate disodium, usually in association with doses of 10-20mg/kg/day. No adverse effects have been traced to this, and it does not constitute grounds for discontinuing therapy. It is apparently due to a drug-related increase in renal tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2-4 weeks post therapy.Patients with significant chronic diarrhoeal disease may experience increased frequency of bowel movements and diarrhoea, particularly at higher doses.Increased or recurrent bone pain at existing Pagetic sites and/or the appearance of pain at sites previously asymptomatic have been reported at a dose of 5mg/kg/day.Fractures are recognised as a common feature in patients with Paget's disease. There has been no evidence of increased risk of fractures at the recommended dose of 5mg/kg/day for six months. At doses of 20mg/kg/day in excess of three months' duration, mineralisation of newly formed osteoid may be impaired and the risk of fracture may be increased. The risk of fracture may also be greater in patients with extensive and severe disease, a history of multiple fractures, and/or rapidly advancing osteolytic lesions. It is therefore recommended that the drug is discontinued when fractures occur and therapy not reinstated until the fracture healing is complete.Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment.The incidence of osteogenic sarcoma is known to be increased in Paget's disease. Pagetic lesions, with or without therapy, may appear by X-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be eva luated carefully to differentiate these from osteogenic sarcoma.Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving bisphosphonates.A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patient with concominant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).While on treatment, these patients should avod invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces risk of osteonecrosis of the jaw.Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Interactions
Food in the stomach or upper portions of the small intestine, particularly materials with a high calcium content such as milk, may reduce absorption of etidronate disodium. Vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium should not be taken within two hours of dosing etidronate disodium.There have been isolated reports of patients experiencing changes in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored.

Adverse Reactions
Gastro-intestinalThe most common effects reported are diarrhoea and nausea. Reports of exacerbation of peptic ulcer with complications in a few patients.Dermatological/hypersensitivityHypersensitivity reactions, including angio-oedema/urticaria, rash and/or pruritus, have been reported rarely.Nervous SystemParesthesia, confusion, have been reported rarely.HaematologicalIn patients receiving etidronate disodium, there have been rare reports of leucopenia, agranulocytosis and pancytopenia.OtherLess common effects believed to be related to therapy include arthropathies (arthralgia and arthritis), and rarely burning of the tongue, alopecia, erythema multiforme and exacerbation of asthma.

Manufacturer
Procter & Gamble Pharmaceuticals UK Limited

Drug Availability
(POM)

Updated
06 May 2009